This is a method for preparing multiwall polymer microspheres, particularly for use in controlled delivery systems.
Controlled delivery of substances, for example, drugs, insecticides, fertilizers, and indicators, can be accomplished using a variety of processes. In one type of delivery system, a polymeric capsule is formed around or incorporating the substance to be delivered. The form and composition of the polymer or polymers determines the method that can be used to incorporate the substance, the environment in which the capsule can be used, and the type of substance which can be incorporated.
One process for preparing microspheres is a hot-melt technique. The melted polymer is mixed with the drug and the mixture suspended in a non-solvent where it is cooled and solidified. The big disadvantage of this process is that only low melting polymers can be used with thermolabile substances.
An alternative method is the solvent evaporation technique, disclosed, for example, by U.S. Pat. No. 3,523,906 to M. N. Vrancken and U.S. Pat. No. 3,960,757 to M. Morishita. These processes have been used extensively to prepare microspheres from biodegradable polymers, as reported in the literature and by H. Jaffe in U.S. Pat. No. 4,272,398. The procedure generally consists of dissolving a polymer in methylene chloride or other volatile solvent, dissolving or suspending a drug in the solution and emulsifying the resulting mixture in an aqueous phase containing an emulsifier. The solvent is then evaporated to produce microspheres containing the substance to be incorporated. The technique of Morishita dissolves a hydrophobic polymer in an organic solvent which is poorly miscible with water and has a boiling point less than water. A substance is dissolved in the polymer solution, the solution emulsified in an aqueous solution of a hydrophilic colloid or surface active agent, and the organic solvent removed by evaporation.
Yet another method used to form microcapsules is phase separation. Essentially, a polymer is forced to precipitate around a core by addition of non-solvent or by addition of a second polymer which is incompatible with the first polymer.
While all of these methods are useful in making microspheres for controlled delivery, they have certain disadvantages. For example, they do not always yield uniform polymer layers. The best one can do at present is to dip microspheres formed of one polymer into a bath of a second polymer and hope each microsphere is coated. In practice, the coatings tend to be non-uniform both with respect to coverage and to thickness. This can be fatal to a system for controlled delivery, as in controlled drug delivery systems requiring linear release of the drug as the polymer degrades in vivo. Further, many of these methods require multiple steps, with increasing quality control problems at each stage. The final yield is frequently low.
Even the fluidized bed method of forming a polymer coating around tablets, where uniform coatings are achievable, has disadvantages. Here, the substance to be incorporated cannot be mixed directly into the coating, especially when the substance is in particle form.
It is therefore an object of the present invention to provide a one step method for manufacturing delivery systems consisting of polymer layers in microspheres form.
It is a further object of the present invention to provide a method for manufacturing polymeric devices from a variety of polymers, including both biodegradable and non-biodegradable polymers.
It is another object of the present invention to provide a method for making polymeric delivery devices where substances in particle form can be incorporated directly into the polymers and which can be conducted at relatively low temperatures to avoid damaging any thermolabile substances to be incorporated.